Both innate cytokines and immune cells contribute to defense against viral infections. Virus is a critical part of pathology during infection. Frequentl, however, elicited immune responses rather than the agent itself cause the detrimental consequences of infection. The cytokine IL-6 is one factor that can play a role in chronic diseases such as rheumatoid arthritis (RA) and may be part of the immune reactivation inflammatory syndrome (IRIS) following successful anti-retroviral therapy (ART) in HIV-infected humans, but the mechanisms by which it leads to disease are not known. Natural killer (NK) cells of the innate immune system play important roles in direct antiviral defense and in shaping the magnitudes of other immune responses to protect against immune-mediated pathology. Different mechanisms inducing and regulating NK cell responses, as well as pathways by which NK cell-mediated effects are delivered, have been elucidated. Nevertheless, nothing is known about how NK cells respond to or regulate IL-6 production. During studies of the expression and function of the signal transducer and activator of transcription 3 (STAT3) in NK cells, this laboratory has discovered a novel, STAT3-dependent role for NK cells in protecting against IL-6-dependent disease during murine cytomegalovirus (MCMV) infection. Based on existing information and our new preliminary studies, our hypothesis is that a cascade response leading to IL-6-mediated disease is regulated (a) by cytokine induction and activation of STAT3 in NK cells, (b) to limit IL-6 production by particular cell types, (c) to in turn protect against IL-6-mediated disease. The studies planned here will test this hypothesis in three specific aims defining: (1) the NK cell functions regulated by STAT3, (2) the pathway(s) by which NK cells regulate IL-6 production, and (3) the mechanism(s) used by IL-6 to induce disease. The studies will characterize conditioning of NK cell responses to a variety of induced cytokines, and changing IL-6 effects on immune and non-immune cell subsets, in the spleen and liver as infection progresses. The work has broad clinical relevance. It promises to greatly advance understanding of the ways by which IL-6 can cause disease and to define yet another important role played by NK cells in protecting against detrimental effects during viral infections.